In one-third of strokes, a definite cause cannot be established. This proposal is for a clinical trial involving patients with a stroke of unknown cause who also have atrial cardiopathy, or abnormal changes in the atrial tissue of the heart. The goal is to compare two different blood-thinning treatments to determine which best prevents recurrent stroke. Under the prevailing clinical paradigm, it is thought that atrial fibrillation?a common disorder of heart rhythm?is required for blood clots to form in the heart's left atrium, from where they can embolize to the brain and cause stroke. Therefore, unless atrial fibrillation is apparent, patients do not receive the types of blood-thinning drugs that best prevent embolic stroke. However, recent research indicates that embolization from the left atrium can occur when there are abnormal changes to atrial tissue and function even before there is atrial fibrillation. These abnormal changes?a condition referred to as atrial cardiopathy? may explain many of the strokes that are currently of unknown cause. Since blood-thinning treatment with an anticoagulant drug such as apixaban has already proven more effective than standard aspirin therapy for preventing stroke from atrial fibrillation, the parallels between atrial fibrillation and atrial cardiopathy suggest that apixaban may also be more effective than aspirin for stroke prevention in patients with atrial cardiopathy and no atrial fibrillation. This application is for a multicenter, biomarker-driven, randomized, double-blind, active-control, phase 3 clinical trial of apixaban versus aspirin in patients who have evidence of atrial cardiopathy and a recent stroke of unknown cause by current criteria. Atrial cardiopathy will be defined as one or more of the following biomarkers: P-wave terminal force in electrocardiogram lead V1 >5,000 V*ms, left atrial size index ?3.0 cm/m2 on echocardiogram, and serum amino terminal pro-B-type natriuretic peptide >250 pg/mL. Standard heart-rhythm monitoring will be performed before enrollment to exclude as thoroughly as possible those patients with atrial fibrillation. Eleven hundred patients will be recruited over 2.5 years at 120 sites in the NINDS StrokeNet consortium. Patients will be followed for a minimum of 1.5 years and a maximum of 4 years for the primary efficacy outcome of recurrent stroke and the primary safety outcomes of major hemorrhage and intracranial hemorrhage. Specific Aim 1 will test the hypothesis that apixaban is superior to aspirin for the prevention of recurrent stroke in patients with atrial cardiopathy. Validation of this hypothesis would have immediate implications for preventing recurrent stroke by identifying a new group of stroke patients who benefit from anticoagulant therapy. Specific Aim 2 will test the hypothesis that the efficacy of apixaban over aspirin increases with the severity of atrial cardiopathy. Validation of this hypothesis would help establish atrial cardiopathy as a stroke risk factor, and thus set the stage for future studies to determine the benefit of treating patients with atrial cardiopathy before they ever have a stroke in the first place.